Autoimmunity
Abstract
The brain ventricles are part of the fluid compartments bridging the CNS with the periphery. Using MRI, we previously observed a pronounced increase in ventricle volume (VV) in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Here, we examined VV changes in EAE and MS patients in longitudinal studies with frequent serial MRI scans. EAE mice underwent serial MRI for up to 2 months, with gadolinium contrast as a proxy of inflammation, confirmed by histopathology. We performed a time-series analysis of clinical and MRI data from a prior clinical trial in which RRMS patients underwent monthly MRI scans over 1 year. VV increased dramatically during preonset EAE, resolving upon clinical remission. VV changes coincided with blood-brain barrier disruption and inflammation. VV was normal at the termination of the experiment, when mice were still symptomatic. The majority of relapsing-remitting MS (RRMS) patients showed dynamic VV fluctuations. Patients with contracting VV had lower disease severity and a shorter duration. These changes demonstrate that VV does not necessarily expand irreversibly in MS but, over short time scales, can expand and contract. Frequent monitoring of VV in patients will be essential to disentangle the disease-related processes driving short-term VV oscillations from persistent expansion resulting from atrophy.
Authors
Jason M. Millward, Paula Ramos Delgado, Alina Smorodchenko, Laura Boehmert, Joao Periquito, Henning M. Reimann, Christian Prinz, Antje Els, Michael Scheel, Judith Bellmann-Strobl, Helmar Waiczies, Jens Wuerfel, Carmen Infante-Duarte, Andreas Pohlmann, Frauke Zipp, Friedemann Paul, Thoralf Niendorf, Sonia Waiczies
Abstract
A possible etiological link between the onset of endemic pemphigus in Tunisia and bites of Phlebotomus (P). papatasi, the vector of zoonotic cutaneous leishmaniasis has been previously suggested. We hypothesized that the immunodominant P. papatasi salivary protein PpSP32 binds to desmogleins (Dsg1 and Dsg3), triggering loss of tolerance to these pemphigus target autoantigens. We here show by Far-Western blot that the recombinant PpSP32 protein (rPpSP32) binds to epidermal proteins with a molecular weight of about 170kDa. Co-immunoprecipitation revealed the interaction of rPpSP32 with either Dsg1 or Dsg3. A specific interaction between PpSP32 and Dsg (1 and 3) was further demonstrated by ELISA assays. Finally, mice immunized with rPpSP32 twice a week exhibited significantly increased levels of anti-Dsg1 and anti-Dsg3 antibodies from day 75 to day 120. Such antibodies were specific for Dsg1 and Dsg3 and were not the result of crossreactivity to PpSP32. Herein, we demonstrated for the first time a specific binding between the PpSP32 and the dsg1 and 3, which might underlie the triggering of anti-Dsg antibodies in patients exposed to sand fly bites. We also confirmed the development of specific anti-Dsg1 and -Dsg3 antibodies in vivo after PpSP32 immunization in mice. Collectively, our results provide evidence that environmental factors, such the exposure to P. papatasi bites, can trigger the development of autoimmune antibodies.
Authors
Soumaya Marzouki, Ines Zaraa, Maha Abdeladhim, Chaouki Ben Abdessalem, Fabiano Oliveira, Shaden Kamhawi, Mourad Mokni, Hechmi Louzir, Jesus Valenzuela, Mélika Ben Ahmed
Abstract
Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in lupus neutrophils over 4 years of follow up and across disease activity levels using 229 patient samples. We demonstrate that DNA methylation profiles in lupus are partly determined by ancestry-associated genetic variations and are highly stable over time. DNA methylation levels in two CpG sites correlated significantly with changes in lupus disease activity. Progressive demethylation in SNX18 was observed with increasing disease activity in African-American patients. Importantly, demethylation of a CpG site located within GALNT18 was associated with the development of active lupus nephritis. Differentially methylated genes between African-American and European-American lupus patients include type I interferon-response genes such as IRF7 and IFI44, and genes related to the NFkB pathway. TREML4, which plays a vital role in toll-like receptor signaling, was hypomethylated in African-American patients and demonstrated a strong cis-meQTL effect among 8855 cis-meQTL associations identified in our study.
Authors
Patrick Coit, Lourdes Ortiz-Fernandez, Emily E. Lewis, W. Joseph McCune, Kathleen Maksimowicz-McKinnon, Amr H. Sawalha
Abstract
Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 (PTPN2) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2-haploinsufficient SKG mice — modeling human carriers of disease-associated variants of PTPN2 — displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor γT (RORγt) — a gut-enriched Treg subset that can undergo conversion into FoxP3–IL-17+ arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2. Ptpn2 haploinsufficiency led to selective joint accumulation of RORγt-expressing Tregs expressing the colonic marker G protein–coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15+ Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15+ exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs.
Authors
Wan-Chen Hsieh, Mattias N.D. Svensson, Martina Zoccheddu, Michael L. Tremblay, Shimon Sakaguchi, Stephanie M. Stanford, Nunzio Bottini
Abstract
Protein phosphatase 2A is a ubiquitously expressed serine/threonine phosphatase which comprises a scaffold, a catalytic and multiple regulatory subunits and has been shown to be important in the expression of autoimmunity. We considered that a distinct subunit may account for the decreased production of interleukin-2 (IL-2) in people and mice with systemic autoimmunity. We show that the regulatory subunit PPP2R2D is increased in T cells from people with systemic lupus erythematosus and regulates IL-2 production. Mice lacking PPP2R2D only in T cells produce more IL-2 because the IL-2 gene and genes coding for IL-2 enhancing transcription factors remain open and the levels of the enhancer phosphorylated CREB are high. Mice with T cell-specific PPP2R2D deficiency display less systemic autoimmunity when exposed to a TLR7 stimulator. While genes related to regulatory T cell function do not change in the absence of PPP2R2D, regulatory T cells exhibit high suppressive function in vitro and in vivo. Because the ubiquitous expression of protein phosphatase 2A cannot permit systemic therapeutic manipulation, the identification of regulatory subunits able to control specific T cell functions opens the way for the development of novel, function-specific drugs.
Authors
Wenliang Pan, Amir Sharabi, Andrew P. Ferretti, Yinfeng Zhang, Catalina Burbano, Nobuya Yoshida, Maria G. Tsokos, George C. Tsokos
Abstract
More than 90% of autoimmune-associated variants are located in noncoding regions, leading to challenges in deciphering the underlying causal roles of functional variants and genes and biological mechanisms. Therefore, to reduce the gap between traditional genetic findings and mechanistic understanding of disease etiologies and clinical drug development, it is important to translate systematically the regulatory mechanisms underlying noncoding variants. Here, we prioritized functional noncoding SNPs with regulatory gene targets associated with 19 autoimmune diseases by incorporating hundreds of immune cell–specific multiomics data. The prioritized SNPs are associated with transcription factor (TF) binding, histone modification, or chromatin accessibility, indicating their allele-specific regulatory roles. Their target genes are significantly enriched in immunologically related pathways and other known immunologically related functions. We found that 90.1% of target genes are regulated by distal SNPs involving several TFs (e.g., the DNA-binding protein CCCTC-binding factor [CTCF]), suggesting the importance of long-range chromatin interaction in autoimmune diseases. Moreover, we predicted potential drug targets for autoimmune diseases, including 2 genes (NFKB1 and SH2B3) with known drug indications on other diseases, highlighting their potential drug repurposing opportunities. Taken together, these findings may provide useful information for future experimental follow-up and drug applications on autoimmune diseases.
Authors
Xiao-Feng Chen, Ming-Rui Guo, Yuan-Yuan Duan, Feng Jiang, Hao Wu, Shan-Shan Dong, Xiao-Rong Zhou, Hlaing Nwe Thynn, Cong-Cong Liu, Lin Zhang, Yan Guo, Tie-Lin Yang
Abstract
Background: Baseline expression of FCRL5, a marker of naïve and memory B cells, was shown to predict response to rituximab (RTX) in rheumatoid arthritis. This study investigated baseline expression of FCRL5 as a potential biomarker of clinical response to RTX in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Methods: A previously validated RT-qPCR-based platform was used to assess FCRL5 expression in patients with GPA/MPA (RAVE trial, NCT00104299). Results: Baseline FCRL5 expression was significantly higher in patients achieving complete response (CR) at 6, 12, and 18 months, independent of other clinical and serological variables, among those randomized to RTX but not CYC/AZA. Patients with baseline FCRL5 expression ≥ 0.01 expression units (termed FCRL5hi) exhibited significantly higher CR rates at 6, 12, and 18 months as compared to FCRL5low subjects (84% vs 57% p=0.016, 68% vs 40% p=0.02 and 68% vs 29% p=0.0009, respectively). Conclusion: Our data taken together suggest that FCRL5 is a biomarker of B cell lineage associated with increased achievement and maintenance of complete remission among patients treated with RTX and warrant further investigation in a prospective manner.
Authors
Kasia Owczarczyk, Matthew D. Cascino, Cecile Holweg, Gaik W. Tew, Ward Ortmann, Timothy W. Behrens, Thomas Schindler, Carol A. Langford, E. William St. Clair, Peter A. Merkel, Robert Spiera, Philip Seo, Cees G.M. Kallenberg, Ulrich Specks, Noha Lim, John H. Stone, Paul Brunetta, Marco Prunotto
Abstract
Scleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the “don’t-eat-me-signal” CD47 and whether blocking CD47 enables the body’s immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated transcription factor JUN and increased promoter accessibilities of both JUN and CD47. Next, we established our scleroderma model, demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1– fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL-6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study demonstrates the efficiency of combining different immunotherapies in treating scleroderma and provides a rationale for combining CD47 and IL-6 inhibition in clinical trials.
Authors
Tristan Lerbs, Lu Cui, Megan E. King, Tim Chai, Claire Muscat, Lorinda Chung, Ryanne Brown, Kerri Rieger, Tyler Shibata, Gerlinde Wernig
Abstract
Gene expression signatures can stratify patients with heterogeneous diseases, such as systemic lupus erythematosus (SLE), yet understanding the contributions of ancestral background to this heterogeneity is not well understood. We hypothesized that ancestry would significantly influence gene expression signatures and measured 34 gene modules in 1566 SLE patients of African ancestry (AA), European ancestry (EA), or Native American ancestry (NAA). Healthy subject ancestry-specific gene expression provided the transcriptomic background upon which the SLE patient signatures were built. Although standard therapy affected every gene signature and significantly increased myeloid cell signatures, logistic regression analysis determined that ancestral background significantly changed 23 of 34 gene signatures. Additionally, the strongest association to gene expression changes was found with autoantibodies, and this also had etiology in ancestry: the AA predisposition to have both RNP and dsDNA autoantibodies compared with EA predisposition to have only anti-dsDNA. A machine learning approach was used to determine a gene signature characteristic to distinguish AA SLE and was most influenced by genes characteristic of the perturbed B cell axis in AA SLE patients.
Authors
Michelle D. Catalina, Prathyusha Bachali, Anthony E. Yeo, Nicholas S. Geraci, Michelle A. Petri, Amrie C. Grammer, Peter E. Lipsky
Abstract
Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder that results in skin fibrosis, autoantibody production and internal organ dysfunction. We previously identified four ‘intrinsic’ subsets of SSc based upon skin gene expression that are found across organ systems. Gene expression regulators that underlie the SSc intrinsic subsets, or are associated with clinical covariates, have not been systematically characterized. Here we present a computational framework to calculate the activity scores of gene expression regulators and identify their associations with SSc clinical outcomes. We find regulator activity scores can reproduce the intrinsic molecular subsets with distinct sets of regulators identified for inflammatory, fibroproliferative and normal-like samples. Regulators most highly correlated with modified Rodnan skin score (MRSS) also varied by intrinsic subset. We identify a subgroup of fibroproliferative/inflammatory SSc patients with more severe pathophenotypes. We further identify a subgroup of SSc patients that had higher MRSS and increased likelihood of interstitial lung disease. Using an independent cohort, we show this group was most likely to show forced vital capacity decline over a period of 36 – 54 months. Our results demonstrate an association between the activation of regulators, gene expression subsets and clinical variables that can identify SSc patients with more severe disease.
Authors
Yue Wang, Jennifer M. Franks, Monica Yang, Diana M. Toledo, Tammara A. Wood, Monique Hinchcliff, Michael L. Whitfield
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